ARDS is a devastating clinical syndrome whose whole therapy has been limited by an inadequate understanding of its basic pathophysiology. My hypothesis is that xanthine oxidase (XO) generated O2 radicals contribute to acute lung injury due to hyperoxia by inactivating tissue associated antiproteases, increasing susceptibility of endothelium to neutrophil elastase (NE) and/or recruiting and activating neutrophils. Preliminary data supports this hypothesis. First, antiprotease activity in perfusates of isolated lungs increases with time, suggesting release of antiproteases. Second, isolated perfused lungs from rats treated with XO inactivators and exposed to hyperoxia a) develop less weight gain than lungs of similarly exposed rats not treated with XO inactivators and b) demonstrate less weight gain when perfused with small doses of NE than similarly exposed and perfused lung from rats not treated with XO inactivators. My immediate specific aims now are to determine whether XO inactivation alters development of acute edematous injury, O2 radical production, neutrophil adherence, tissue and/or perfusate associated antiprotease activity, elastase activity in vivo, susceptibility to NE, and/or neutrophil mediated lung injury in isolated perfused lungs from rats exposed to hyperoxia. The significance of this project is to improve understanding of the basic mechanisms of acute lung injury, such as that seen in ARDS.